Mammalian L1 elements (LINE-1) replicate (retrotranspose) by copying their RNA transcripts into DNA which is then integrated into the genome. L1 elements have been replicating and evolving in mammalian genomes since before the mammalian radiation 100 MYA. L1 elements account for 17% of the human genome and cause up to 0.2% of the genetic defects. In addition, they likely catalyze the retroposition of the highly repeated SINE (Alu) families and processed pseudogenes. The ~6 kb human L1 element has four regions: A 5? UTR (untranslated region) has a regulatory function; ORF I encodes an RNA binding protein; ORF II encodes the L1 cDNA replicase; the 3? UTR contains a conserved G-rich polypurine motif. We found that both rodent and human L1 elements evolve rapidly with novel families continually replacing older ones. Since most of the copies of past L1 families are retained, modern genomes contain both ancestral and modern L1 families. The relics of the extinct L1 families can yield phylogenetic information about the host species and important genetic parameters such as its neutral mutation rate. L1 insertions generated by currently replicating families provide robust polymorphic genetic markers for analyzing population structure. We continued our analysis of the human Ta L1 family focusing on isolating the insertions produced its Ta1 subfamily which we recently discovered. Since this family is currently amplifying in humans, many of its inserts should be polymorphic and thus useful as genetic characters for recent population history. So far we have cloned 286 Ta1-containing loci from a representative of 3 different ethnic groups. We were able to evaluate 201 of them and found that at least 95 were polymorphic. Of these 56 (57%) are novel inserts since they are not present in the current human data base. Interestingly, 14 of these polymorphisms are unique to the individual from whom they were cloned and we are now examining their distribution within each relevant ethnic group. Our results showing that most of the genetic loci that once contained potentially active (i.e., full length, FL) ancestral L1 elements are no longer present in modern humans has now been published. These FL L1 elements represented four different L1 families (L1PA2-L1PA5) that amplified from between 8 and 25 MYA. Thus, there has been continual purifying selection against these active L1 elements. This implies that not only did the ancestral active L1 elements impose a significant genetic load on early humans, but that the currently active Ta family may also do so. In an attempt to understand why novel L1 families continually arise and replace existing families, we determined the nucleotide changes that characterized the evolution of each of the 4 ancestral families mentioned above. We found that a region of ORF1 underwent an episode of positive (adaptive) selection which then ceased. The adaptive evolution involves a region of ORF1 shown by others (using mice L1) to be involved in protein-protein interaction. This episode of adaptive evolution could represent an accommodation to evolutionary changes elsewhere in the element or in the host. In case of the latter, adaptation to a host factor required for L1 replication or to by pass host repression could be involved. Experiments are now underway to test all of these possibilities.